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An in depth analysis of gold nanoparticle (AuNP) synthesis and size tuning, utilizing carbon monoxide (CO) gas as a reducing agent, is presented for the first time. The sizes of the AuNPs are tunable from ~4 to 100 nm by altering the concentration of HAuCl4 and inlet CO gas-injection flow rate. It is also found that speciation of aqueous HAuCl4, prior to reduction, influences the size, morphology, and properties of AuNPs when reduced with CO gas. Ensemble extinction spectra and TEM images provide clear evidence that CO reduction offers a high level of monodispersity with standard deviations as low as 3%. Upon synthesis, no excess reducing agent remains in solution eliminating the need for purification. The time necessary to synthesize AuNPs, using CO, is less than 2 min.

Gold nanoparticle-mediated photothermal therapy (PTT) has shown great potential for the treatment of cancer in mouse studies and is now being evaluated in clinical trials. For this therapy, gold nanoparticles (AuNPs) are injected intravenously and are allowed to accumulate within the tumor via the enhanced permeability and retention (EPR) effect. The tumor is then irradiated with a near infrared laser, whose energy is absorbed by the AuNPs and translated into heat. While reliance on the EPR effect for tumor targeting has proven adequate for vascularized tumors in small animal models, the efficiency and specificity of tumor delivery in vivo, particularly in tumors with poor blood supply, has proven challenging. In this study, we examine whether human T cells can be used as cellular delivery vehicles for AuNP transport into tumors. We first demonstrate that T cells can be efficiently loaded with 45 nm gold colloid nanoparticles without affecting viability or function (e.g. migration and cytokine production). Using a human tumor xenograft mouse model, we next demonstrate that AuNP-loaded T cells retain their capacity to migrate to tumor sites in vivo. In addition, the efficiency of AuNP delivery to tumors in vivo is increased by more than four-fold compared to injection of free PEGylated AuNPs and the use of the T cell delivery system also dramatically alters the overall nanoparticle biodistribution. Thus, the use of T cell chaperones for AuNP delivery could enhance the efficacy of nanoparticle-based therapies and imaging applications by increasing AuNP tumor accumulation.

Purpose: To test the hypothesis that diffusion-weighted (DW)-PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) MRI provides more accurate liver tumor necrotic fraction (NF) and viable tumor volume (VTV) measurements than conventional DW-SE-EPI (spin echo echo-planar imaging) methods., Materials and Methods: Our institutional Animal Care and Use Committee approved all experiments. In six rabbits implanted with 10 VX2 liver tumors, DW-PROPELLER and DW-SE-EPI scans were performed at contiguous axial slice positions covering each tumor volume. Apparent diffusion coefficient maps of each tumor were used to generate spatially resolved tumor viability maps for NF and VTV measurements. We compared NF, whole tumor volume (WTV), and VTV measurements to corresponding reference standard histological measurements based on correlation and concordance coefficients and the Bland-Altman analysis., Results: DW-PROPELLER generally improved image quality with less distortion compared to DW-SE-EPI. DW-PROPELLER NF, WTV, and VTV measurements were strongly correlated and satisfactorily concordant with histological measurements. DW-SE-EPI NF measurements were weakly correlated and poorly concordant with histological measurements. Bland-Altman analysis demonstrated that DW-PROPELLER WTV and VTV measurements were less biased from histological measurements than the corresponding DW-SE-EPI measurements., Conclusion: DW-PROPELLER MRI can provide spatially resolved liver tumor viability maps for accurate NF and VTV measurements, superior to DW-SE-EPI approaches. DW-PROPELLER measurements may serve as a noninvasive surrogate for pathology, offering the potential for more accurate assessments of therapy response than conventional anatomic size measurements., ((c) 2008 Wiley-Liss, Inc.)

Purpose: To assess the relationship between cumulative hepatic lobar radiation dose and liver toxicities in patients with hepatocellular carcinoma (HCC) treated with multiple sessions of yttrium-90 radioembolization., Materials and Methods: Forty-one patients with HCC (age range, 46-82 years) underwent radioembolization with 90Y. Patients were classified according to the Okuda scoring system. All patients received single liver lobar treatments on two or more occasions according to standard clinical 90Y embolization protocol. Cumulative radiation dose to each liver lobe was measured and patients were followed to assess liver toxicities. Statistical analysis was performed with the Student t test and Kaplan-Meier analysis., Results: Patients with Okuda stage I disease received more treatments than those with Okuda stage II disease (mean, 2.65 vs 2.24; P<.05). For average cumulative radiation dose, patients with Okuda stage I disease received 247 Gy (range, 88-482 Gy) and those with Okuda stage II disease received 198 Gy (range, 51-361 Gy; P<.05). A total of 13 toxicities occurred in seven patients (16%). Patients with Okuda stage I disease were given a greater cumulative dose than patients with Okuda stage II disease before worsening of liver function: 390 Gy versus 196 Gy (P<.005). For patients with Okuda stage I disease, a higher cumulative radiation dose was associated with occurrence of one or more toxicities: 222 Gy (no toxicities) versus 390 Gy (>or=1 toxicity; P<.005). No correlation between cumulative radiation dose and liver toxicities existed in patients with Okuda stage II disease. The maximum tolerated dose was between 222 and 390 Gy. Median survival times were 660 and 431 days for patients with Okuda stage I and stage II disease, respectively., Conclusions: Patients with HCC can tolerate high cumulative radiation doses with 90Y therapy. Compared with patients with Okuda stage II disease, patients with Okuda stage I disease tolerate a higher cumulative radiation dose without liver toxicity, but liver toxicities increase with increasing cumulative radiation doses.

Tumor growth and metastasis require that tumor cells must have either the potential to shift genetically or epigenetically between proliferative and invasive phenotypes or both phenotypes simultaneously. In the present study, we demonstrated that neuroblastoma growth and invasion were distinct processes that were carried out by proliferative and invasive phenotypes of tumor cells, respectively. Two subpopulations from human neuroblastoma cell line were isolated: highly invasive (HI) cells and low-invasive (LI) cells. HI and LI cells had different proliferative rate and metastatic ability in vitro and in vivo. In addition, they had distinct activated signal pathways and sensitivities to chemotherapy drugs. Affymetrix microarray and quantitative reverse transcriptase-polymerase chain reaction revealed that visinin-like protein-1 (VSNL-1) mRNA in HI cells was significantly higher than that in LI cells. We also observed that VSNL-1 was over-expressed in tumor specimens from patients with distant organ metastases compared with those without metastases. Furthermore, the invasive and proliferative phenotypes of neuroblastoma cells could be exchanged by regulation of VSNL-1 expression in vitro and in vivo. Up-regulation of VSNL-1 potentiated the anoikis-resistant ability of neuroblastoma cell. The expression of anoikis inhibitor TrkB, intracellular adhesion molecule 1, major histocompatibility complex class I, CD44 and CD44v6 was associated with VSNL-1 level. These results suggested that distinct roles of proliferative and invasive phenotypes contributed to neuroblastoma progression and strongly demonstrated that VSNL-1 played a very important role in neuroblastoma metastasis.

Purpose: To test the hypothesis that transcatheter arterial embolization (TAE) of VX2 rabbit liver tumors increases the expression of hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor that regulates the expression of pro-angiogenic genes., Materials and Methods: VX2 tumors were implanted in the livers of eight New Zealand white rabbits. Once tumor growth was seen at T2-weighted turbo spin-echo magnetic resonance (MR) imaging, four of the eight rabbits underwent TAE with 45-150-mum polyvinyl alcohol particles. The remaining four rabbits served as non-TAE controls. The TAE end point was stasis of antegrade blood flow. All rabbits were sacrificed for tumor harvest 2 hours after TAE. Tumor tissue and corresponding normal liver tissue in each rabbit liver were stained with anti-human HIF-1alpha monoclonal antibody and reviewed with light microscopy. Percentages of stained viable tumor and normal liver cells were compared by using the Mann-Whitney U test (alpha=0.05)., Results: In eight rabbits with 24 discrete liver tumors, the mean percentage (+/-standard deviation) of positive HIF-1alpha-stained cells in the TAE group was greater than that in the control group (19%+/-7.0 vs 12%+/-8.0, respectively) (P=.05). Normal liver tissue in both the TAE and control groups showed no HIF-1alpha staining., Conclusion: Although HIF-1alpha is not expressed in normal rabbit liver parenchyma-even after TAE-HIF-1alpha expression is present in implanted VX2 rabbit liver tumors and significantly increased in lesions that have undergone embolization.